Gotta Verena, Csajka Chantal, Glauser Antonia, Berger Christoph, Pfister Marc, Paioni Paolo
Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, 4031 Basel, Switzerland.
Pediatric Clinical Pharmacy, University of Basel Children's Hospital, 4031 Basel, Switzerland.
Pharmaceutics. 2025 Apr 22;17(5):544. doi: 10.3390/pharmaceutics17050544.
Optimal dosing of cefepime in infants 1-2 months remains undefined. : We aimed to quantify the risk of potentially neurotoxic exposure with high-dose cefepime (50 mg/kg/8 h) in infants 1-2 months of age, as compared to adjacent age groups (neonates, infants 2-12 months) and lower dose treatment (50 mg/kg/12 h). : Pharmacometric simulations were performed using two published population pharmacokinetic models combined with demographic data, including serum creatinine, for neonates and infants ≤ 12 months. Adult-derived safety thresholds for potential neurotoxicity were defined as steady-state trough concentration (C) > 20 or > 35 mg/L, respectively. The corresponding probability of target attainment (PTA) was calculated as free concentration, 50% of the time during the dosing interval above the minimal inhibitory concentration (MIC) breakpoint of 8 mg/L ( spp.) (50% fT>MIC). : The predicted risk of C > 20 (>35) mg/L under high-dose cefepime was 40-54% (12-22%) in infants 1-2 months while providing high PTA (100%). It was predicted to be 1.3-1.7 fold higher in neonates (model 1), and reduced 1.8-2.4 fold in infants 2-12 months (model 1), or to be similar (model 2), respectively. Both models predicted approximately 2-4 fold reduced risk using lower dose treatments while maintaining high PTA (≥97%). : The risk of potential neurotoxic concentrations in infants > 1 month treated with cefepime 50 mg/kg/8 h is high if defined by adult safety thresholds. Lower dose cefepime in infants 1-2 months could be a safe option without compromising PTA, if defined as 50% fT>MIC. Achievement of 100% fT>MIC may require prolonged infusion time even under high-dose treatment. Future research is required to evaluate potentially age-dependent safety thresholds.
1至2个月大婴儿的头孢吡肟最佳剂量仍未明确。我们旨在量化1至2个月大婴儿使用高剂量头孢吡肟（50mg/kg/8小时）与相邻年龄组（新生儿、2至12个月大婴儿）以及低剂量治疗（50mg/kg/12小时）相比潜在神经毒性暴露的风险。使用两个已发表的群体药代动力学模型结合人口统计学数据（包括新生儿和≤12个月大婴儿的血清肌酐）进行药代动力学模拟。成人潜在神经毒性的安全阈值分别定义为稳态谷浓度（C）>20或>35mg/L。相应的达标概率（PTA）计算为游离浓度，即给药间隔期间50%的时间高于8mg/L（肺炎链球菌）的最低抑菌浓度（MIC）断点（50% fT>MIC）。在1至2个月大婴儿中，高剂量头孢吡肟下C>20（>35）mg/L的预测风险为40 - 54%（12 - 22%），同时提供高PTA（100%）。在新生儿中预测高出1.3 - 1.7倍（模型1），在2至12个月大婴儿中降低1.8 - 2.4倍（模型1）或相似（模型2）。两个模型均预测使用低剂量治疗风险降低约2 - 4倍，同时保持高PTA（≥97%）。如果按照成人安全阈值定义，1个月以上使用50mg/kg/8小时头孢吡肟治疗的婴儿出现潜在神经毒性浓度的风险很高。如果定义为50% fT>MIC，1至2个月大婴儿使用较低剂量头孢吡肟可能是一个安全选择且不影响PTA。即使在高剂量治疗下，要达到100% fT>MIC可能需要延长输注时间。未来需要进行研究以评估潜在的年龄依赖性安全阈值。
